Previously, non-alcoholic fatty liver disease was believed to be a benign disease that does not progress. However, it was revealed that even non-drinkers develop inflammation similar to alcoholic hepatitis and show hepatic fibrosis histology, and now the non-alcoholic fatty liver disease is known as a disease with poor prognosis. In particular, metabolic syndromes due to obesity, diabetes, or the like have been drawing attention in recent years. It is becoming a common view that nonalcoholic steatohepatitis (NASH) is one of such syndromes. However, the mechanism remains unclear, and effective methods and/or agents for treating NASH have not been established. This is partly because NASH is due to human lifestyle-related diseases, and thus appropriate experimental animals have not been established.
For the development of effective methods and agents for treating NASH, it is essential to elucidate the pathological condition of NASH, which progresses to lethal diseases such as liver cirrhosis and liver cancer. However, experimental animals that are currently used as a NASH model mouse in research include single-gene modified mice such as leptin receptor-deficient mice (Non-patent Document 1), hepatocyte-specific Pten-deficient mice (Non-patent Document 2), and retinoic acid receptor α dominant-negative transgenic mice (Non-patent Document 3), and mice induced with a special diet such as a methionine/choline-deficient diet (Non-patent Document 4). However, the human pathogenesis differs from that in the genetically-modified mice in which a single-gene mutation is responsible for the development and progression of the pathological condition, and is unlikely to be due to only the intake of a particular nutrient. Furthermore, insulin resistance and hepatic fibrosis cannot be simultaneously monitored in these mice. Furthermore, the ALT, an index in serobiochemical analysis, is only slightly elevated in mice that develop fibrosis, and therefore several mouse tissue slices are required to assess their pathological condition. Conversely, the pathological condition is assumed to be different from that of human because ALT is elevated to a markedly high level. Furthermore, the pathological condition recovers spontaneously after treatment. This makes it difficult to test and assess drugs for their efficacy. Thus, for developing methods and agents for treating NASH, it is desirable to establish an experimental animal model that is compatible with the human clinical condition.
Although various studies have been conducted, there is no experimental animal exhibiting pathological conditions similar to those of human. Thus, under the current circumstances, it is difficult to conduct detailed screening to elucidate the pathogenesis or to establish therapeutic methods.